There is considerable interindividual variability in estrogen metabolism which results in a wide range of plasma concentrations in postmenopausal women on estrogen replacement therapy. Estradiol, the most potent endogenous estrogen, is metabolized by a series of oxidative transformations to much less potent metabolites. The most important of these oxidations, C-2 hydroxylation is performed by both CYP1A2 and CYP3A. CYP1A2 and CYP3A are cytochrome P450s which are present in the liver and are responsible for the metabolism of endogenous steroids, a large number of medications, detoxification of poisons and activation of carcinogens. CYP3A is also highly expressed in the intestine, where it plays a role in first pass metabolism. Ethnic origin, diet and medications have been shown to result in altered drug concentrations and clinically significant alterations in drug effects for many of the drugs metablized by the P450 enzymes. Cigarette smoking decreases estradiol concentrations by increasing the C-2 hydroxylation metabolic pathway which appears to result in a reduced risk of endometrial cancer, earlier natural menopause and increased osteoporsis in female smokers. Given the large number of women on estrogen replacement therapy, it is therefore surprising that very little is known concerning other factors that affect estrogen metabolism and plasma concentrations. There is marked interindividual variability in estrogen metabolism and plasma concentrations in postmenopausal women on estrogen replacement therapy that is due to differences in the activity of CYP3A and CYP1A2 and that this variability can have an important impact on estrogen effects. The implication of such findings would be that optimization of estrogen dose would have a positive impact on women's health.